Exudative (or wet) AMD (age-related macular degeneration) is the leading cause of severe vision loss and blindness among older Americans. While Lucentis(r) and off-label use of Avastin(r)-the clear market leaders in wet AMD- improve vision in some patients for a period of time, they do not represent the complete solution. Both of these drugs target a single growth factor, VEGF, and appear to exert most of their beneficial effect via an anti-permeability action resulting in resolution of retinal edema, but the underlying choroidal neovascular (CNV) lesion does not markedly involute, and the chronic disease typically continues to progress. Growing evidence suggests that the bioactive lipid S1P could contribute to both the early and late stages of maladaptive retinal remodeling associated with wet AMD. S1P has a pronounced non-VEGF-dependent pro-angiogenic effect and several other effects not exhibited by VEGF. For example, S1P stimulates migration, proliferation and survival of fibroblasts, endothelial cells, pericytes and inflammatory cells- the same cells that participate in the multiple maladaptive processes of exudative AMD. Thus, inhibiting the action of S1P could be a novel and effective therapeutic treatment for wet AMD that may offer significant advantages over exclusively anti-VEGF approaches (or act synergistically with them) to address the complex processes and multiple steps that ultimately lead to visual loss. Lpath's iSONEP drug candidate is a humanized monoclonal antibody directed against S1P. iSONEP acts as a molecular sponge to selectively absorb S1P from the extracellular fluid, lowering the effective concentration of S1P. Anti-S1P mAbs have demonstrated efficacy in several animal models of wet AMD;moreover, iSONEP is well tolerated by mice, rabbits, non-human primates, and humans alike. Lpath has recently completed a Phase I clinical trial in wet AMD patients, and, based on preliminary data (unaudited), the trial showed encouraging signs of biological effect on key parameters of disease. After a single dose of iSONEP, a majority of patients exhibited improvement, including marked reduction in retinal edema and related retinal thickness, complete regression of the underlying CNV lesion (which the VEGF inhibitors rarely do), and near-complete resolution of RPE detachment (which the VEGF inhibitors normally do not do). Most patients had previously received multiple anti-VEGF treatments, but were not responding well, suggesting that iSONEP may have effects that are independent of these treatments. The specific aims of this proposal are to conduct (i) a Phase I lead-in clinical trial to assess dosing and safety of iSONEP in combination with Lucentis, with supporting toxicological and bio-distribution studies in animals, (ii) a Phase II clinical trial to assess the efficacy of the combination therapy, and (iii) several nonclinical animal studies to assess additional applications of iSONEP beyond wet AMD, like diabetic retinopathy, dry AMD and PVR, where there are significant unmet medical needs. Success with these aims will demonstrate iSONEP's potential to affect the multiple underlying pathologies of wet AMD (and perhaps other ocular conditions) and thereby provide a more-complete solution to a complex and disabling disease. PUBLIC HEALTH RELEVANCE Exudative (or wet) AMD (age-related macular degeneration) is the leading cause of severe vision loss and blindness among older Americans. While Lucentis(r) and off-label use of Avastin(r)-the clear market leaders in wet AMD-improve vision in some patients for a period of time, they do not represent the complete solution. Lpath's innovative drug candidate, iSONEP, targets a bioactive lipid, S1P, and may represent the next generation of wet-AMD treatments, as well as potentially addressing other disabling ocular disorders such as diabetic retinopathy, dry AMD and proliferative vitreoretinopathy.